Recurrence of local estrogen receptor positive (ER+) breast cancer in the form of advanced/metastatic disease despite adjuvant anti-estrogen therapy affects many thousands of women per year. Recurrence is associated with endocrine-therapy resistance and is usually fatal. There is a need to better predict which patients would do well without adjuvant treatment, benefit from adjuvant treatment, or respond poorly to adjuvant therapy to minimize overtreatment as well as to avoid prolonged, non-curative therapies. We discovered a novel breast cancer tumor suppressor called G0/G1 switch gene 2 (G0S2). We identified that G0S2 expression is frequently repressed in human breast cancer and that this repression is associated with increased rates of recurrence, especially for ER+ patients undergoing adjuvant anti-estrogen therapy. We demonstrate that G0S2 can antagonize oncogenic transformation in part by repressing MYC activation and that G0S2 loss causes activation of MYC, PI3K and mTOR signaling signatures and resistance to PI3K and mTOR inhibitors. MYC, PI3K and mTOR activation are known mechanisms of anti-estrogen resistance and we found that G0S2 overexpression in breast cancer cells leads to repression of mTOR signaling and increased sensitivity to PI3K and mTOR inhibitors. MYC and PI3K/mTOR activation have recently been implicated in mediating anti-estrogen resistance and MYC-driven breast tumors are resistant to MEK and PI3K/mTOR pathway inhibitors. Our overall hypothesis is that G0S2 suppresses MYC and PI3K/mTOR signaling in breast cancer and that the presence of G0S2 promotes more effective responses to existing therapies targeting ER+ breast cancer leading to inhibition of recurrence. Our project utilizes in vitro and in vivo molecular, cellular and biochemical based studies as well as bioinformatic approaches. The objective of this small grant proposal is to further solidify G0S2 anticancer effects by developing in vitro and in vivo models that will be used in current and future studies to definitively establish a role for G0S2 in the repression of breast cancer progression, recurrence, and in enhancing and predicting responses to targeted growth factor pathway and antiestrogen therapies. Since very little is known about the molecular functions of G0S2, the proposal is also designed to develop leads concerning the direct mechanism(s) of G0S2 actions. In order to uncover new, alternative targeted therapies for breast cancers that fail adjuvant therapy it is vital to further understand the mechanisms of recurrence. Our discovery that G0S2 expression is frequently repressed in human breast cancer and that this repression is associated with recurrence and activation of pathways linked to anti-estrogen therapy resistance may have major impact in predicting recurrence and mechanisms of sensitivity and resistance to many therapies targeting these pathways that are currently in clinical development.